X-57331760-G-A

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_Moderate BP6 BS2

The NM_174912.4(FAAH2):c.575G>A(p.Arg192Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000455 in 1,209,645 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 23 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000063 (0 hom., 5 hem., cov: 22)
  • Exomes 𝑓: 0.000044 (0 hom. 18 hem.)
• Consequence: FAAH2 NM_174912.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 2.27

Genes affected

FAAH2 (HGNC:26440): (fatty acid amide hydrolase 2) This gene encodes a fatty acid amide hydrolase that shares a conserved protein motif with the amidase signature family of enzymes. The encoded enzyme is able to catalyze the hydrolysis of a broad range of bioactive lipids, including those from the three main classes of fatty acid amides; N-acylethanolamines, fatty acid primary amides and N-acyl amino acids. This enzyme has a preference for monounsaturated acyl chains as a substrate. Alternate splicing results in multiple transcript variants encoding distinct isoforms. [provided by RefSeq, Jul 2017]

ACMG classification

Verdict is Benign. Variant got -7 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.08137539).
• BP6: Variant X-57331760-G-A is Benign according to our data. Variant chrX-57331760-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 252796.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1}.
• BS2: High Hemizygotes in GnomAd at 5 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FAAH2	NM_174912.4	c.575G>A	p.Arg192Gln	missense_variant	4/11	ENST00000374900.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FAAH2	ENST00000374900.5	c.575G>A	p.Arg192Gln	missense_variant	4/11	1	NM_174912.4	P1

Frequencies

GnomAD3 genomes AF: 0.0000628 AC: 7 AN: 111533 Hom.: 0 Cov.: 22 AF XY: 0.000148 AC XY: 5 AN XY: 33713

Gnomad AFR AF: 0.0000652

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000748

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000564

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000601 AC: 11 AN: 183101 Hom.: 0 AF XY: 0.0000591 AC XY: 4 AN XY: 67637

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000365

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000262

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000612

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000437 AC: 48 AN: 1098068 Hom.: 0 Cov.: 30 AF XY: 0.0000495 AC XY: 18 AN XY: 363456

Gnomad4 AFR exome AF: 0.0000379

Gnomad4 AMR exome AF: 0.0000568

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000351

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000309

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000627 AC: 7 AN: 111577 Hom.: 0 Cov.: 22 AF XY: 0.000148 AC XY: 5 AN XY: 33767

Gnomad4 AFR AF: 0.0000651

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000751

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000564

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000529

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000149 AC: 1

ExAC AF: 0.0000741 AC: 9

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Oct 26, 2021	The c.575G>A (p.R192Q) alteration is located in exon 4 (coding exon 4) of the FAAH2 gene. This alteration results from a G to A substitution at nucleotide position 575, causing the arginine (R) at amino acid position 192 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
Likely benign, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Nov 06, 2015	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.66
Cadd	Benign	14
Dann	Benign	0.91
DEOGEN2	Benign	0.25	T
FATHMM_MKL	Benign	0.34	N
LIST_S2	Benign	0.83	T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.081	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.4	L
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.47	T
PROVEAN	Uncertain	-2.6	D
REVEL	Benign	0.091
Sift	Benign	0.18	T
Sift4G	Benign	0.19	T
Polyphen		0.32	B
Vest4		0.089
MVP		0.63
MPC		0.00084
ClinPred		0.040	T
GERP RS		2.3
Varity_R		0.089
gMVP		0.52

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs201024763; hg19: chrX-57358193; COSMIC: COSV100887081;